Pathologic N2 Non-small-cell Lung Cancer Research Articles

A narrative review of postoperative adjuvant radiotherapy for non-small cell lung cancer.

To summarize the principal studies investigating the role of postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC) and to discuss the recent major breakthroughs deriving from the Lung ART trial, in order to provide a real-world scenario of the management of resected NSCLC patients. Surgery followed by platinum-based chemotherapy remains the mainstay of adjuvant treatments for completely resected stage II and IIIA NSCLC. Less consistent is the employment of PORT, as no significant benefit was clearly identified from the previous published meta-analysis. Furthermore, the recent results of Lung ART trial questioned for the first time the efficacy of PORT for pathological N2 (pN2) NSCLC patients. Hence, the need to define if PORT still has a role for resected NSCLC and which subgroup of patients could benefit most from this treatment. A literature search of PubMed was performed to identify publications, including prospective and retrospective clinical studies, meta-analysis and systematic review of PORT for NSCLC. No limit concerning years of publication or publication status were applied. Only papers using the English language were selected. The ESMO 2020 and ESMO 2021 online resources were used to analyze the Lung ART trial results. The authors provide a narrative summary of the findings and implications of these studies and how they improve the clinical practice. PORT was considered the standard of care for patients with completely resected pN2 NSCLC based on the results of an old meta-analysis that did not demonstrate a detrimental effect. The more recent randomized phase III Lung ART trial concluded that PORT could not anymore be recommended for pN2 NSCLC as a significant benefit in terms of 3 years disease-free survival (DFS) was not reached and an increased rate of radiotherapy related toxicity was observed. Retrospective studies suggest a possible role of PORT for incompletely resected NSCLC patients and those with an extranodal extension (ENE), but this issue needs to be reinforced from randomized prospective trials. The extensive publication of Lung ART trial is largely awaited to define if there is a role of PORT for resected NSCLC patients.

Lung cancer with PET/CT-defined occult nodal metastasis yields favourable prognosis and benefits from adjuvant therapy: a multicentre study.

To investigate the surgical prognosis and efficacy of adjuvant therapy in non-small cell lung cancer (NSCLC) with occult lymph node metastasis (ONM) defined by positron emission tomography/computed tomography (PET/CT). A total of 3537 NSCLC patients receiving surgical resection were included in this study. The prognosis between patients with ONM and evident nodal metastasis, ONM patients with and without adjuvant therapy was compared, respectively. ONM was associated with significantly better prognosis than evident nodal metastasis whether for patients with N1 (5-year OS: 56.8% versus 52.3%, adjusted p value = 0.267; 5-year RFS: 44.7% versus 33.2%, adjusted p value = 0.031) or N2 metastasis (5-year OS: 42.8% versus 32.3%, adjusted p value = 0.010; 5-year RFS: 31.3% versus 21.6%, adjusted p value = 0.025). In ONM population, patients receiving adjuvant therapy yielded better prognosis comparing to those without adjuvant therapy (5-year OS: 50.1% versus 33.5%, adjusted p value < 0.001; 5-year RFS: 38.4% versus 22.1%, adjusted p value < 0.001). ONM defined by PET/CT identifies a unique clinical subtype of lung cancer, ONM is a favorable prognostic factor whether for pathological N1 or N2 NSCLC and adjuvant therapy could provide additional survival benefits for ONM patients.

The impact of order with radiation therapy in stage IIIA pathologic N2 NSCLC patients: a population-based study

BackgroundThe aim of this study was to investigate the optimal order of radiation therapy in patients affected by stage IIIA pathologic N2 (IIIA/N2) non-small-cell lung cancer (NSCLC) and to identify its potential risk factors.Methods17,654 (8786 men and 8868 women) diagnosed with NSCLC stage IIIA-N2 from 2004 to 2015 patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Among the relevant clinical parameters, we evaluated overall survival (OS), lung cancer-specific survival (LCSS) and other variables such as age, sex and tumor size in patients who were treated with different combinations of surgery and radiotherapy strategies.ResultsWe discovered that surgery benefit in younger IIIA/N2 NSCLC patients (age ≤ 75), and compared with surgery only, preoperative radiotherapy significantly improved the survival rate most (p < 0.001). When we performed the OS and LCSS analysis in the subgroup of patients’ age > 75 years old, who underwent postoperative radiotherapy (PORT) had the highest survival rate (p < 0.001). Multivariate analyses showed that the following parameters had a negative impact on survival: female sex, older age, no chemotherapy, large tumor size, high tumor grade, no surgery or radiotherapy.ConclusionsIn IIIA/N2 NSCLC patients, surgery, radiotherapy and chemotherapy were associated with improved OS and LCSS. Younger patients underwent surgical resection and chemotherapy, the main population we studied, benefited most from preoperative radiotherapy in all orders with radiation therapy (p < 0.001). In patients more than 75 years old, there was no clear benefit from only surgery, and PORT was recommended in case of having surgery.

Results of video-assisted thoracic surgery versus thoracotomy in surgical resection of pN2 non-small cell lung cancer in a Chinese high-volume Center.

To investigate the short-term outcomes and long-term oncological efficacy of video-assisted thoracic surgery (VATS) for surgical treatment of pN2 non-small cell lung cancer (NSCLC) compared with open thoracotomy (OT). We retrospectively collected data from 1034 patients who underwent pulmonary resection and systemic lymph node dissection for pathological N2 NSCLC from September 2005 to December 2017 (536 patients in VATS group and 498 patients in OT group). Propensity score matching was applied to reduce the confounding effects. Factors affecting survival were assessed by Kaplan-Meier estimates and Cox regression analysis. The VATS procedure was associated with shorter operative time compared with the OT procedure (147.96 ± 58.91min vs. 165.34 ± 58.91min, P < 0.001). No significant difference was identified between the two groups in the number of dissected mediastinal lymph nodes (MLNs) and number of dissected MLNs stations. More patients after VATS procedure received postoperative adjuvant therapy (83.4% vs. 75.5%, P = 0.002). At a median follow-up of 36 (range 4-150) months, comparing VATS procedure and OT procedure, no significant differences were noted in 5-year DFS (20.7% vs. 22.5%, P = 0.89) and 5-year OS (30.7% vs. 34.5%, P = 0.821). The VATS procedure was not found to be an independent predictor of DFS (hazard ratio, 0.986; 95% CI, 0.809 to 1.202) or OS (hazard ratio, 0.977; 95% CI 0.802 to 1.191). In this large propensity-matched comparison, the VATS procedure offered comparable short-term outcomes and long-term oncological efficacy for patients with pN2 NSCLC when compared with OT procedure.

Survival benefit of skip metastases in surgically resected N2 non-small cell lung cancer: A multicenter observational study of a large cohort of the Chinese patients

IntroductionN2 non-small cell lung cancer (NSCLC) without N1 involvement, also known as skip metastases (pN0N2), has been suggested as a subgroup of heterogeneous N2 disease with better survival. This real-world observational study aimed to elucidate the prognostic impacts of skip N2 metastases using a large number of pathologic N2 NSCLC from 10 participating centers in China. Materials and methodsMedical records of pN2 NSCLC patients after surgical resection at 10 thoracic surgery centers between January 2014 and September 2017 were retrospectively reviewed based on the LinkDoc database. Clinical data on patient demographics, tumor characteristics, treatments and clinical outcomes were collected. Overall survival of patients with and without skip metastases was evaluated and compared by Kaplan-Meier method and Log-rank test. Cox proportional hazard model was established to identify potential prognostic predictors. Subgroup analysis was carried out to further explore the prognostic significance of skip metastases. ResultsAmong 2653 surgically resected N2 patients, 881 (33.2%) had skip metastases. Patients with skip N2 had a significant better overall survival (P = 0.0019). Multivariate COX regression analysis showed borderline significance of skip metastases (HR = 0.81, 95%CI: 0.645–1.017, P = 0.0698) after adjustment for other covariates. Other independent prognostic predictors included smoking history, tumor location, stage and N2 station involved (P < 0.05). Subgroup analysis demonstrated significant survival benefits of skip N2 in most subpopulations. ConclusionsThis study suggested a prognostic benefit of skip N2 metastases in real world practice. Further subdivision of N2 disease is warranted for better patient management and prognostic prediction (NCT 03429192).

P1.08-060 Survival of Patients with Unsuspected N2 (Stage IIIA) Non-Small Cell Lung Cancer

There are few studies evaluating the N2 pattern and outcomes when a patient with non–small cell lung cancer (NSCLC) unexpectedly is found to have N2 disease at the time of thoracoscopy or thoracotomy. The objective of this study was to determine the survival of patients who have completely resected, nonsmall-cell, stage IIIA, lung cancer from unsuspected (nonimaged) N2 disease. A retrospective review of NSCLC patients treated with lobectomy for clinically unsuspected mediastinal nodal disease (cT1-cT3 cN0-cN1, pN2 disease) at our institution between January 2008 and December 2011 was conducted. All patients underwent computed tomography scan with contrast, R0 resection with complete thoracic lymphadenectomy, and had unsuspected, pathologic N2 NSCLC. Positron emission tomography scan or invasive staging was added in the attending physician’s choice. Unsuspected pN2 disease was found in 10.9% of patients (31 out of 284) who underwent lobectomy as primary therapy for cT1-cT3 cN0-cN1 NSCLC. Of these, cN0pN2 and cN1pN2 were 9.6% (26 out of 270) and 35% (5 out of 14), respectively. Compare to cN0 group, unsuspected pN2 was more frequent in the cN1group (p=.0023). In terms of the pattern of metastasis, multiple and single pN2 was observed similarly in cN0 and cN1 group (p=.9484). The 5-year overall survival of the entire unsuspected pN2 was 68.5%, and cN0pN2 cohort tended to have better prognosis than cN1pN2 cohort (71.1% (cN0pN2) vs. 50.0% (cN1pN2); p=.0898). No significant difference in 5y-OS between unsuspected single and multiple pN2 could be seen; (70.5% (single) vs. 66.7% (multiple); p=.07803). This analysis suggests that, in the setting of unsuspected pN2 NSCLC, proceeding with anatomic surgery does not appear to compromise outcomes. As unsuspected pN2 disease was more frequent in cN1 cohort and revealed poor prognosis, perioperative invasive mediastinal staging and additional therapy should be considered.

P3.01-022 Impact of Histologic Subtype and Spread through Air Spaces (STAS) in Stage III (N2) Lung Adenocarcinoma: Topic: Morphology

Approximately 15% of patient with non-small cell lung cancer (NSCLC) is present with stage III (N2) disease. The patient prognosis after complete resection for pathological N2 NSCLC remains a significant concern. Currently, the new World Health Organization classification of lung cancers was revised and newly prescribed to describe the presence of each histologic subtype in adenocarcinoma (ADC) and the Spread Through Air Spaces (STAS). The purpose of this study is to examine the relationship between histologic subtype and patient outcome, especially for metastatic lymph node, and clinicopathologic features of STAS in stage III (N2) lung ADC according to new WHO classification retrospectively. All available tumor slides from patients with pathological N2, surgically resected lung ADC (1998-2013) were reviewed. Each tumor was evaluated by comprehensive histologic subtyping according to new WHO classification, and the percentage of each histologic component was recorded in 5% increments. We reviewed the histologic subtype in the N2 lymph nodes and relationship between main tumor and N2 lymph nodes. Recurrence-free probability (RFP) and overall survival (OS) were estimated using the Kaplan-Meier method. 78 patients met inclusion criteria (55% men; median age: 68yrs; 76 stageIIIA/2 stageIIIB, 77 lobectomy). The 5-year RFP and OS in N2 lung ADC were 27.8%, 66.8%, respectively. The histologic subtypes such as acinar, micropapillary and solid components in the main tumor were significantly seen in the N2 lymph nodes (P < 0.001, P < 0.05, P < 0.05, respectively). STAS was identified in 48 patients (61.5%) and significantly associated with recurrence (5-year RFP: 18.4% vs. 43.8%, P < 0.05). STAS was significantly associated with presence of micropapillary component (≥ 5%) and lymphatic invasion in the main tumor (P < 0.001). Presence of acinar, micropapillary and solid component in the main tumor are associated with metastasizing to lymph nodes. Presence of STAS was significantly associated with increased risk of recurrence in stage III (N2) lung adenocarcinoma.

The impact on the prognosis of unsuspected N2 disease in non-small-cell lung cancer: indications for thorough mediastinal staging in the modern era.

Predicting the prognosis of advanced non-small-cell lung cancer (NSCLC) patients who present with clinically unsuspected N2 is very different due to the heterogeneity of this cohort. Thus, this study was undertaken to identify the clinicopathological features and survival of patients with clinical N0 or N1 and pathological N2, namely, unsuspected N2. Among 239 patients with pathological N2 NSCLC, we reviewed the cases of 92 (38.5%) patients who showed unsuspected N2. The prognosis was investigated using the Kaplan-Meier method and a Cox regression model. The 5-year overall survival (5yOS) of the patients with unsuspected N2 was 51.2%. Based on a multivariate analysis, age and 18F-fluorodeoxyglucose (FDG) uptake in the lymph nodes were significant prognostic factors of unsuspected N2 (p=0.0081, 0.0228, respectively). The 5yOS of PET-negative unsuspected N2 (n=68) was 58.9%, whereas that of PET-positive unsuspected N2 (n=24) was 29.7% (p=0.0026). Furthermore, the 5yOS of PET-negative unsuspected N2 was significantly better than that of both clinical and pathological N2s (i.e., suspected N2; n=60; 5yOS, 42.1%; p=0.0051), while no significant difference was observed between PET-positive unsuspected N2 and suspected N2 (p=0.6325). A preoperative evaluation of the lymph nodes by PET/CT has a potential benefit in predicting the prognosis. A thorough evaluation of the lymph nodes is, therefore, needed if the lymph nodes show an FDG uptake, even in cases that show a clinical N0 status on thin section CT scans.

The Role of Cancer-Testis Antigens as Predictive and Prognostic Markers in Non-Small Cell Lung Cancer

BackgroundCancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival.MethodsWe studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs.ResultsNY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28–5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07–0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression.ConclusionsNY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

Postoperative Radiotherapy for Patients With Completely Resected Pathologic N2 Non–Small-Cell Lung Cancer: A Retrospective Analysis

BackgroundAdjuvant radiotherapy in non–small-cell lung cancer (NSCLC) is still controversial. The purpose of this retrospective study was to evaluate the role of postoperative radiotherapy (PORT) in terms of local control and survival in pathologic N2 NSCLC. Patients and MethodsFrom January 2003 to December 2008, 66 patients with pathologic N2 NSCLC received PORT. Mediastinal lymph node metastases were classified into single (12 patients) or multiple (54 patients) stations. All patients received conformal radiation therapy, with a median total dose of 50.4 Gy. Target volumes included the bronchial stump, ipsilateral hilum, all pathologically involved lymph node regions, and all the lymph nodes between 2 noncontiguous pathologic nodal stations. The pattern of failure was considered as locoregional or systemic, or a combination of both. Locoregional failure was defined as in field or out of field. ResultsMedian follow-up time was 34.9 months (range 3.5-62.8 months). Local control was 80% at 12 months, 77.2% at both 24 and 36 months, and 72.1% at 60 months. The pattern of failure was locoregional in 3 patients (1 out of field and 2 in field) and systemic in 25 patients, with 12 patients presenting both locoregional and distant disease. Overall survival at 12, 36, and 60 months was 77%, 44%, and 37%, respectively. Median survival time was 34 months. The number of pathologically involved lymph node stations was a prognostic factor for local control (P = .05), cancer-specific survival (CSS) (P = .04), and disease-free survival (DFS) (P = .04). ConclusionDespite the limitations of the present study, mainly represented by its retrospective nature, our data support the role of PORT in terms of locoregional control and overall survival benefit; the number of involved mediastinal lymph nodes represents a significant prognostic factor in patients with pathologic N2 NSCLC.

Nuclear survivin in pN2 nonsmall cell lung cancer: prognostic and clinical implications

Patients with N2 nonsmall cell lung cancer (N2-NSCLC) represent heterogeneous groups. Survivin is a member of the inhibitor of apoptosis family. If N2-NSCLC patients could be stratified, based on survivin expression and/or its relation to cell cycle proteins, into homogeneous subgroups, certain therapies could be selected for those patients. Survivin expression in 78 surgically resected primary pathological N2-NSCLC tumours was evaluated using immunohistochemistry. Relationships of survivin expression to overall survival, clinical features and expression of six cell cycle-related proteins (pRb, cyclin D1, p16(INK4A), p53, p21(Waf1) and Ki-67) were analysed. Nuclear survivin and the number of mediastinal lymph node (LN) stations were independent prognostic factors. The patient group with combined negative survivin/single mediastinal LN station were the most favourable prognostic group, and was related to the clinical nodal factor. Indeed, patients with negative survivin/low Ki-67 labelling indices had the best survival, especially in nonsquamous histopathology. The current authors conclude that nuclear survivin is strongly related to lymph node metastasis and proliferative potentials in pathological N2 nonsmall cell lung cancer patients. Pre-operative N2 nonsmall cell lung cancer patients with combined negative nuclear survivin and a single mediastinal lymph node station, or low proliferative indices, particularly in clinical N0-1 disease and nonsquamous histopathology, respectively, are expected to have a favourable post-operative prognosis and may be candidates for primary resection.

Induction Chemotherapy with Cisplatin, Vinorelbine, and Mitomycin-C Followed by Surgery for Patients with Pathologic N2 Non–Small-Cell Lung Cancer

PURPOSEThe treatment strategy for patients with non–small-cell lung cancer (NSCLC) involving ipsilateral mediastinal lymph nodes is still controversial. We performed a phase II feasibility study of induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC. PATIENTS AND METHODSPatients with mediastinoscopy- positive stage IIIA N2 NSCLC received 2 cycles of cisplatin 80 mg/m2, vinorelbine 25 mg/m2, and mitomycin-C 8 mg/m2. Patients without progressive disease underwent thoracotomy and lobectomy with lymph node dissections 2-4 weeks later. RESULTSFrom January 2000 to July 2004, 24 eligible patients (15 men, 9 women) were enrolled. Induction chemotherapy was completed as planned in 23 patients (95.8%). Hematological toxicity was the primary grade 3/4 toxicity. Twelve (50%) patients achieved a partial response. Twenty-three patients underwent surgical resection, and complete resection was achieved in 22 patients (95.7%). There were no surgery-related deaths. Pathologic complete response in metastatic lymph nodes was achieved in 5 patients. With a median follow-up of 5.4 years (range, 2.88-7.7 years), the estimated 5-year survival was 51.8% (95% CI, 41.3-62.3) and progression-free survival was 46.6% (95% CI, 36–57.2). CONCLUSIONInduction chemotherapy followed by surgery for patients with pathologic N2 NSCLC was feasible and associated with high response to lymph node metastasis and good survival.

Survival following resection of clinically occult N2 non small cell lung cancer: Dalton R, Keller S. Department of Cardiothoracic Surgery, Mount Sinai Medical Center, One Gustave L Levy Place, New York 10029-6574. J Cardiovasc Surg 1994;35:Suppl 1–6:13–17

The role of resection in Stage IIIA (N2) non-small cell lung cancer (NSCLC) remains controversial despite reported survival rates of 25-40%. This study was undertaken to identify factors associated with a high risk of treatment failure after resection of clinically occult Stage IIIA (N2) NSCLC: Such prognostic factors may identify high risk patients as candidates for future clinical trials of multimodality lung cancer treatment and be important stratification factors in such trials.The clinical and pathological records of 32 patients with clinical NO pathologic N2 NSCLC who underwent lobectomy (n = 17), pneumonectomy (n = 12), or bilobectomy (n = 3) and complete mediastinal lymph node dissection at Fox Chase Cancer Center from 1987 to 1991 were reviewed. A multivariate analysis of clinical and pathologic variables was performed.Median follow-up was 15 months (range 5-55). Fifty-nine percent have recurred and 44% have died. Median disease free and overall survival were 16 and 19 months, respectively. Two year disease free and overall survival were 24% and 43%, respectively. No patient with more than one level of mediastinal lymph node metastases survived two years free of disease. Univariate and multivariate analysis revealed a longer disease free survival for those receiving adjuvant radiation therapy (19 vs 5 months) but no increase in overall survival.This experience with clinically occult Stage IIIA (N2) NSCLC suggests that multiple levels of mediastinal lymph node metastases predict treatment failure in patients following resection and that adjuvant mediastinal radiation improves disease free but not overall survival.